Objective To investigate the expression of macrophage migration inhibitory factor (MIF) in complex regional pain syndrome Ⅰ (CRPS Ⅰ) rat model and the possible efficacy of MIF blockage in treatment of CRPS Ⅰ. Methods Fifty healthy male SD rats were randomly divided into the following 5 groups: control, sham, model, DMSO control, and ISO-1(inhibitor of MIF) treatment. CRPS1 models were created in the last 3 groups; rats in the ISO-1 treatment group were subcutaneously treated with ISO-1 dissolved in 10 μl 5% DMSO at 1 mg/(kg·d) for 14 d. DMSO control group was only given 10 μl 5% DMSO. The pain threshold and thickness of the hindpaws were measured before and after treatment and were compared. The levels of MIF protein were examined in the serum, skin, spinal cord, sciatic nerve, and cerebrospinal fluid using ELISA and Western blotting analysis.Results Rats in the model group had noticeable hindpaw edema and significantly decreased pain threshold compared with the baselihe and that of the control group(P<0.01) . The hindpaw edema and pain threshold were significantly improved in ISO-1 treatment group compared with those in the model group(P<0.05). MIF levels in the serum, skin, spinal cord, cerebrospinal fluid and sciatic nerve were higher in the model, DMSO control, and ISO-1 groups compared with those in the control group (P<0.05 or P<0.01). Conclusion MIF is a key inflammatory factor of CRPS Ⅰ, and anti-MIF treatment might be a new therapy for human CRPS Ⅰ.